Spiro[isoxazalidine-3,2&#39;-tricyclo[3.3.1.13,7 ] decanes]

ABSTRACT

The compounds are of the class of adamantanyl isoxazolidine derivatives useful as anti-inflammatory, antihypoxia, antimicrobial and anticonvulsant agents. Exempliary of a species of the compounds is 2 methyl-5-n-hexyl-spiro[isoxazolidin-3,2&#39;-tricyclo[3.3.1.1 3 ,7 ] decane].

FIELD OF THE INVENTION

This invention relates to new adamantanyl isoxazolidine derivatives. More particularly, it relates to derivatives of spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]. Some of these compounds, when tested, were found to have anti inflammatory activity against carrageenan induced edema in a laboratory animal model and, in some instances, antimicrobial (N. gonorrhoeae), antihypoxia, analgesic and anticonvulsant activity in animal testing.

STATEMENT OF THE INVENTION

This invention includes derivatives of a spiro [isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]having the structural formula ##STR1## wherein R is a lower alkyl group; R¹ is a substituent selected from the group consisting of C₁ -C₂₄ alkyl, an amino(C₁ -C₄ alkyl), a carboxyl, a phenyl, a (C₁ -C₄ alkoxy)carbonyl, a (halogenated acetamido)C₁ -C₄ alkyl, a hydroxy(C₁ -C₄ alkyl), an aminocarbonyl, a (C₁ -C₄ alkylamino)carbonyl, an [(aminocarbonyl)amino]C₁ -C₄ alkyl, a [[(C₁ -C₄ alkylamino)carbonyl]amino]C₁ -C₄ alkyl, a [[(phenylamino)thiocarbonyl]amino]C₁ -C₄ alkyl, a (C₁ -C₂₄ alkanoyloxy)C₁ -C₄ alkyl and a (C₁ -C₂₄ alkanoylamino)C₁ -C₄ alkyl; R² is hydrogen or a lower alkoxycarbonyl; and R³ is hydrogen or hydroxy.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of this invention are derivatives of spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]of the structural formula as set forth above.

The R substituent of the formula is preferably a lower alkyl group (C₁ to about C₈ alkyl), more preferably an alkyl group having less than 5 carbon atoms. R¹ is preferably a C₁ -C₂₄ alkyl, most preferably a C₁ -C₇ alkyl or C₁₅ -C₁₇ alkyl; an aminoalkyl having less than 5 carbons, most preferably aminomethyl; carboxyl; phenyl; a C₁ -C₄ alkoxycarbonyl; a (halogenated acetamido)C₁ -C₄ alkyl, for example, (trifluoroacetamido)methyl; a hydroxyalkyl having less than 5 carbons, most preferably hydroxymethyl; aminocarbonyl; (C₁ -C₄ alkylamino) carbonyl; [(aminocarbonyl)amino]C₁ -C₄ alkyl, most preferably [(aminocarbonyl)amino]methyl; [(C₁ -C₄ alkylamino-carbonyl) amino]C₁ -C₄ alkyl, most preferably [(methylamino-carbonyl) amino]methyl; [[(phenylamino)thiocarbonyl]amino]C₁ -C₄ alkyl, most preferably [[(phenylamino)thiocarbonyl]amino]methyl; (C₁ -C₂₄ alkanoyloxy) C₁ -C₄ alkyl, for example (n-hexadecanoyloxy) methyl; and a (C₁ -C.sub. 24 alkanoylamino)C₁ -C₄ alkyl, for example, (n-hexadecanamido)methyl. R² is hydrogen or a lower alkoxycarbonyl, preferably where the alkyl group has less than 5 carbon atoms, and R³ is hydrogen or a hydroxy group.

In general, the adamantanyl isoxazolidine derivatives of this invention are prepared by condensing 2-adamantanone in an inert atmosphere with an appropriate N-substituted hydroxylamine, usually dissolved in an inert organic solvent, to provide the corresponding adamantyl nitrone. The latter compound is then reacted with a substituted olefin and undergoes 1,3-dipolar cycloaddition to provide one of the adamantanyl isoxazolidine derivatives of this invention.

EXAMPLES

The following examples demonstrate the preparation of representative compounds of this invention.

EXAMPLE 1

2-Methyl-5-n-hexyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane]was prepared as follows:

Under a nitrogen atmosphere, 18.03 g (0.12 mole) of 2-adamantanone and 10.34 g (0.13 mole) of N-methylhydroxylamine were dissolved in 300 ml of absolute ethanol. Sodium bicarbonate (10.99 g, 0.13 mole) was added and the resulting suspension refluxed for 3 hours. Upon cooling to room temperature, the solvent was removed in vacuo, 250 ml of toluene were added, and the suspension was filtered. C₆ H₁₃ CH═CH₂ (1-octene) (48 ml, 2.5 equiv) was added to the filtrate and the solution was refluxed under nitrogen for 40 hours. Removal of the solvent gave a yellow oil which crystallized from ethyl ether saturated with hydrogen chloride, giving 26.25 g (67%) of the hydrochloride salt of 2-methyl-5-n-hexyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]as a white solid. Recrystallization from ethyl acetate gave an analytical sample, m.p. 134-136° C.

Anal. Calcd. for C₁₉ H₃₄ ClNO:C, 69.59; H, 10.45; N, 4.27; Cl, 10.81. Found: C, 69.21; H, 10.84; N, 4.22; Cl, 10.66.

This compound showed antihypoxic and anticonvulsant activity at a dosage level of 200 mg/kg.

EXAMPLE 2

2-Methyl-5-methoxycarbonyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane]was prepared in accordance with the procedure of Example 1 except that the substituted olefin was ##STR2## (methyl acrylate). Recrystallization from methanol gave an analytical sample, m.p. 166-170° C.

Anal. Calcd. for C₁₅ H₂₄ ClNO₃ : C; 59.69; H,8.02; N,4.64;Cl, 11.75. Found: C,59.77; H,8.30; N,4.66; Cl,12.26.

This compound showed antimicrobial (N.gonorrhoeae), anti-inflammatory and antihypoxic activity at dosage levels ranging from 50 to 200 mg/kg.

EXAMPLE 3

2-Methyl-5-methyl-4-methoxycarbonyl spiro[isoxazolidine-3, 2'-tricyclo[3.3.1.1³,7 ]decane]was prepared in accordance with the procedure of Example 1 except that the substituted olefin ##STR3## was (methyl crotonate). Recrystallization from methanol gave an analytical sample, m.p. 127-129° C.

Anal. Calcd. for C₁₆ H₂₅ NO₃ : C,68.79; H,9.02; N,5.01. Found: C,69.06; H,9.25; N,4.98. This compound showed anti-inflammatory activity at 50 mg/kg dosage.

EXAMPLE 4

2-Methyl-5-hydroxymethyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1³,7 ]decane]was prepared in accordance with the procedure of Example 1 except that the substituted olefin was HOH₂ C--CH═CH₂ (allyl alcohol). Recrystallization from methanol gave an analytical sample, m.p. 93-96° C.

Anal. Calcd. for C₁₄ H₂₃ NO₂ : C,70.35; H,9.77; N,5.90. Found: C,71.38; H,9.69; N,5.92. This compound showed anticonvulsant activity at 190 mg/kg dosage.

EXAMPLE 5

2-Methyl-5-(aminocarbonyl)-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]was prepared in accordance with the procedure of Example 1 except that the substituted olefin was ##STR4## (acrylamide). Recrystallization from methanol gave an analytical sample, m.p. 182-183° C.

Anal. Calcd. for C₁₄ H₂₂ N₂ O₂ : C,67.17; H,8.86; N,11.19. Found: C,67.38; H,9.23; N,11.25. This compound showed antihypoxic activity at 200 mg/kg dosage.

EXAMPLE 6

2-Ethyl-5-phenyl-spiro[oxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane was prepared in accordance with the procedure of Example 1 except that the substituted olefin was C₆ H₅ CH═CH₂ (styrene) and the N-methylhydroxylamine was replaced with N-ethylhydroxylamine. Recrystallization from methanol gave an analytical sample, m.p. 91-94° C.

Anal. Calcd. for C₂₀ H₂₇ NO: C,80.76; H,9.15; N,4.71. Found C,80.79; H,9.30; N,4.67. This compound showed anticonvulsant activity at 135 mg/kg.

EXAMPLE 7

2-Methyl-5-(trifluoroacetamido)methyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]was prepared in accordance with the procedure of Example 1 except that the substituted olefin was ##STR5## (N-allyl trifluoroacetamide). Recrystallization from methanol gave an analytical sample, m.p. 144-147° C.

Anal. Calcd. for C₁₆ H₂₃ F₃ N₂ O₂ : C,57.82; H,6.97; N,8.43; F,17.15. Found: C,57.89; H,7.02; N,8.43; F,17.26. This compound showed antihypoxic activity at 100 mg/kg.

EXAMPLE 8

2-Methyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]-5-carboxylic acid was prepared as follows:

Aqueous sodium hydroxide (1N, 4.0 ml) was added to a solution of 1.01 g (3.8 mmoles) of the compound prepared in Example 2 in 20 ml of dioxane. The reaction was stirred for 45 min, then the solvent was removed. The residue was dissolved in water and acidified to pH 1.0 with dilute hydrochloric acid; a precipitate formed and was collected to give 0.73 g (76%) of 2-methyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1³,7 ]decane]-5-carboxylic acid. Recrystallization from isopropanol gave an analytical sample, m.p. 156-159° C. (decomp).

Anal. Calcd. for C₁₄ H₂₁ NO₃ : C, 66.91; H, 8.42; N, 5.57. Found: C, 66.82; H, 9.07; N, 5.54. This compound shows antihypoxic activity at 100 mg/kg.

EXAMPLE 9

2-Methyl-5-(aminomethyl)-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1³,7 ]decane]was prepared as follows:

To a solution of 16.62 g (0.050 mole) of the compound of Example 7 in 200 ml of ethanol was added 60 ml of 1N aqueous sodium hydroxide. After stirring for 3 hours, the reaction was diluted with water and extracted with methylene chloride. The organic layer was washed with water, dried and evaporated. The remaining oil was crystallized from ethanol saturated with HCl gas as the dihydrochloride salt of 2-methyl-5-(aminomethyl)-spiro-[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane]. Yield:12.74 g (82%), m.p. 209-229° C. (decomp).

Anal. Calcd. for C₁₄ H₂₆ Cl₂ N₂ O: C, 54.37; H, 8.47; N, 9.06; Cl, 22.93. Found: C, 54.44; H, 8.88; N, 9.06; Cl, 22.66. This compound shows antihypoxic activity at 100 mg/kg.

EXAMPLE 10

2-Methyl-5-[[(methylamino)carbonyl]amino]methyl-spiro ]isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]was prepared as follows:

Under a nitrogen atmosphere, methyl isocyanate (1.5 ml, 1.5 equiv) was added to a solution of 3.90 g (16.5 moles) of a compound prepared in accordance with Example 9 in 150 ml of ether, at 5° C. After 21/2 hours, the precipitate was collected and crystallized from methanol; Yield: 3.55 g (73%), m.p. 176-180° C.

Anal. Calcd. for C₁₆ H₂₇ N₃ O₂ : C, 65.50; H, 9.27; N, 14.32. Found: C, 65.36; H, 9.58; N, 14.26. This compound showed anticonvulsant activity at 350 mg/kg dosage.

EXAMPLE 11

2-Methyl-5-[[(phenylamino)thiocarbonyl]amino]methyl-spiro [isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]was prepared as follows:

Under a nitrogen atmosphere, 3.3 ml (1.1 equiv) of phenylisothiocyanate was added to a solution of 5.91 g (25.0 mmoles) of a compound prepared in accordance with Example 9 in 100 ml of ether. The reaction mixture was stirred for 1 hour at 5° C., then for 2 hours at room temperature. The product was collected by filtration. Yield: 9.03 g (97%). Recrystallization from ethyl acetate gave an analytical sample, m.p. 186-189° C. (decomp).

Anal. Calcd. for C₂₁ H₂₉ N₃ OS: C, 67.89; H, 7.81; N, 11.31. Found: C, 67.99; H, 7.96; N, 11.37. This compound showed anticonvulsant activity at 400 mg/kg.

EXAMPLE 12

2-Methyl-5-(n-hexadecanamido)methyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1³,7 ]decane]was prepared as follows:

Under a nitrogen atmosphere, 5.91 g (25.0 mmoles) of a compound prepared in accordance with Example 9 and 5.2 ml (1.5 equiv) of triethylamine were dissolved in 100 ml of dry tetrahydrofuran. The solution was cooled in an ice bath and then 7.56 g (1.1 equiv) of palmitoyl chloride was added dropwise over 10 min. The resulting suspension was stirred for 1 hour at 5° C., for 2 hours at room temperature, then poured into ice-water and extracted with methylene chloride. The organic layer was dried and the solvent removed. Crystallization from ethyl acetate gave the desired product as white granules. Yield: 9.99 g (84%), m.p. 74-76° C.

Anal. Calcd. for C₃₀ H₅₄ N₂ O₂ : C, 75.90; H, 11.46; N, 5.90. Found: C, 75.85; H. 11.54; N, 5.78. This compound showed antihypoxic activity at 25 mg/kg dosage.

EXAMPLE 13

2-Methyl-5-(n-hexadecanoyloxy)methyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane]was prepared using the compound of Example 4 as follows:

palmitoyl chloride (5.90 g., 0.0215 mole) was added to a solution of 2-methyl-5-(hydroxymethyl)-spiro-[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane](4.75 g, 0.0200 mole) and triethylamine (3.0 ml, 0.0216 mole) in 50 ml of dry tetrahydrofuran, while stirring at 10° C. under a nitrogen atmosphere. The resulting suspension was then stirred for 20 hours at room temperature, poured into 150 ml of ice-water and extracted with 200 ml of ether. The organic layer was dried over anhydrous magnesium sulfate, filtered and the solvent removed in vacuo, leaving a yellow oil. Flash chromatography on silica gel, using 98:2 methylene chloride/methanol as eluant, gave, after crystallization from pentane, 6.64 g (70%) of the desired product as white granules, m.p. 38-44° C.; calculated for C₃₀ H₅₃ NO₃ : C,75.74; H, 11.23; N, 2.94. Found: C, 76.13; H, 11.53; N, 2.75. This compound was found to have antihypoxic activity at 100 mg/kg dosage.

EXAMPLE 14

Methyl 5¹ -hydroxy-2-methyl spiro[isoxazolidine-3-2'-tricyclo [3.3.1.1³,7 ]decane]-5-carboxylate was prepared as follows:

1-Hydroxytricyclo[3.3.1.1³,7 ]decan-4-one was first prepared from tricyclo[3.3.1.1³,7 ]decane]-2-one by the procedure of L. Vodicka et al. Sb. Vys. Sk. Chem. Technol. Praz., Technol. Paliv 1978 D39, 357. A suspension of 1-hydroxy-tricyclo [3.3.1.1³,7 ]decane-4-one (3.85 g, 0.0232 mole), N-methylhydroxylamine hydrochloride (2.00 g, 1.01 equiv.) and sodium bicarbonate in 100 ml of ethanol was refluxed for 2 hours under a nitrogen atmosphere. Upon cooling to room temperature, the suspension was filtered and the solvent removed in vacuo. The oily residue was dissolved in 100 ml of benzene, 4.0 ml (0.044 moles) of methyl acrylate was added, and the solution was refluxed for 16 hours under a nitrogen atmosphere. The reaction was cooled to room temperature, the solvent removed in vacuo, and the residual oil was flash chromatographed on silica gel, using ethyl acetate as the eluant, to give 2.77 g (42%) of the product as an oil (mixture of isomers); calculated for C₁₅ H₂₃ NO₄ : C, 64.04; H, 8.24; N, 4.98. Found, C, 63.98; H, 8.06; N, 4.18.

This compound was found to have anti-inflammatory activity at 50 mg/kg dosage.

EXAMPLE 15

The following alkanes:

(a) 1-hexene,

(b) 1-decene,

(c) 1-dodecene

(d) 1-hexadecene,

(e) 1-octadecene,

(f) 1-eicosene,

(g) and styrene;

are used in the procedure of Example 1 to replace 1-octene to prepare the following compounds:

(a) 2-methyl-5-n-butyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane], m.p. 145-148° C.

(b) 2-methyl-5-n-octyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane], m.p. 103-106° C.

(c) 2-methyl-5-n-decyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1.sup. 3,7 ]decane], m.p. 129-134° C.

(d) 2-methyl-5-n-tetradecyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane], m.p. 111-114° C.

(e) 2-methyl-5-n-hexadecyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane], m.p. 108-111° C.

(f) 2-methyl-5-n-octadecyl-spiro[isoxazolidine-3,2'-tricyclo[3.3.1.1³,7 ]decane], m.p. 110-113° C.

(g) 2-methyl-5-phenyl-spiro[isoxazolidine-3,2'-tricyclo [3.3.1.1³,7 ]decane], m.p. 85-88° C.

Of the above compounds, (a), (b), (e), and (g) were found to have anti-convulsant and antihypoxic activity, (a) had antimicrobial activity, and (d) had anti-inflammatory activity. 

We claim:
 1. A spiro [isoxazolidine -3,2'-tricyclo[3.3.1.1.³,7 ]decane]compound having the structural formula ##STR6## wherein R is a C₁ -C₄ alkyl group; R¹ is a substituent selected from the group consisting of C₁ -C₂₄ primary alkyl, an amino C₁ -C₄ alkyl, a carboxyl, a phenyl, a C₁ -C₄ alkoxy carbonyl, a (trifluoroacetamido)C₁ -C₄ alkyl, a hydroxy C₁ -C₄ alkyl, an aminocarbonyl, a (C₁ -C₄ alkylamino) carbonyl, an [(aminocarbonyl)amino]C₁ -C₄ alkyl, a [[(C₁ -C₄ alkylamino)carbonyl]amino]C₁ -C₄ alkyl, a [[(phenylamino)thiocarbonyl]amino]C₁ -C₄ alkyl, a (C₁ -C₂₄ alkanoyloxy)C₁ -C₄ alkyl and a (C₁ -C₂₄ alkanoylamino) C₁ -C₄ alkyl; R² is hydrogen or a C₁ -C₄ alkoxycarbonyl; and R³ is hydrogen or hydroxy, and the hydrochloride salt of said compound.
 2. The compound of claim 1 wherein R is an alkyl having less than 5 carbon atoms.
 3. The compound of claim 2 wherein R² and R³ are hydrogen.
 4. The compound of claim 2 wherein R¹ is C₁ -C₂₄ alkyl.
 5. The compound of claim 2 wherein R¹ is a C₁ -C₄ alkoxycarbonyl.
 6. The compound of claim 5 wherein R¹ is methoxycarbonyl.
 7. The compound of claim 2 wherein R¹ is a hydroxy(C₁ -C₄ alkyl).
 8. The compound of claim 7 wherein R¹ is hydroxymethyl.
 9. The compound of claim 2 wherein R¹ is C₁ -C₄ alkyl, R² is C₁ -C₄ alkoxycarbonyl and R³ is hydrogen.
 10. The compound of claim 9 wherein R¹ is methyl and R² is methoxycarbonyl.
 11. The compound of claim 2 wherein R¹ is a (C₁ -C₂₄ alkanoyloxy)C₁ -C₄ alkyl.
 12. The compound of claim 2 wherein R¹ is a (C₁ -C₂₄ alkanoylamino)C₁ -C₄ alkyl.
 13. The compound of claim 2 wherein R¹ is phenyl.
 14. The compound of claim 2 wherein R¹ is aminocarbonyl.
 15. The compound of claim 2 wherein R¹ is carboxyl.
 16. The compound of claim 4 wherein R² is hydrogen and R₃ is hydroxy.
 17. The compound of claim 15 wherein R¹ is methoxycarbonyl.
 18. The compound of claim 1 in the form of its hydrochloride salt.
 19. The compound of claim 18 wherein R is an alkyl group having less than 5 carbon atoms, R¹ is methoxycarbonyl and R² and R³ are hydrogen.
 20. The compound of claim 18 wherein R is a C₁ -C₄ alkyl group, R¹ is an alkyl group having 15 to 17 carbon atoms, and R² and R³ are hydrogen. 